Gut microbiota alterations affect glioma growth and innate immune cells involved in tumor immunosurveillance in mice.

Glioma is a CNS tumor with few therapeutic options. Recently, host microbiota has been involved in the immune modulation of different tumors, but no data are available on the possible effects of the gut-immune axis on brain tumors. Here, we investigated the effect of gut microbiota alteration in a syngeneic (GL261) mouse model of glioma, treating mice with two antibiotics (ABX) and evaluating the effects on tumor growth, microbe composition, natural killer (NK) cells and microglia phenotype. We report that ABX treatment (i) altered the intestinal microbiota at family level, (ii) reduced cytotoxic NK cell subsets, and (iii) altered the expression of inflammatory and homeostatic proteins in microglia. All these findings could contribute to the increased growth of intracranial glioma that was observed after ABX treatment. These results demonstrate that chronic ABX administration alters microbiota composition and contributes to modulate brain immune state paving the way to glioma growth.

Nocardia farcinica Meningitis Masquerading as Central Nervous System Metastasis in a Child With Cerebellar Pilocytic Astrocytoma.

Juvenile pilocytic astrocytoma, the most common pediatric central nervous system (CNS) neoplasm, characteristically displays an indolent growth pattern and rarely demonstrates metastatic dissemination. Reports of infections mimicking CNS metastatic disease are also rare and can impact treatment. We report the youngest known case of a child with a CNS Nocardia farcinica infection who had a known cerebellar pilocytic astrocytoma, review other infections that may masquerade as CNS neoplasms, and discuss N. farcinica CNS infections.

Microbiota and glioma: a new perspective from association to clinical translation.

Gliomas pose a significant challenge in oncology due to their malignant nature, aggressive growth, frequent recurrence, and complications posed by the blood-brain barrier. Emerging research has revealed the critical role of gut microbiota in influencing health and disease, indicating its possible impact on glioma pathogenesis and treatment responsiveness. This review focused on existing evidence and hypotheses on the relationship between microbiota and glioma from progression to invasion. By discussing possible mechanisms through which microbiota may affect glioma biology, this paper offers new avenues for targeted therapies and precision medicine in oncology.

Revealing the link between gut microbiota and brain tumor risk: a new perspective from Mendelian randomization.

Background: Recent studies have shown that gut microbiota may be related to the occurrence of brain tumors, but direct evidence is lacking. This study used the Mendelian randomization study (MR) method to explore the potential causal link between gut microbiota and brain tumors. Method: We analyzed the genome-wide association data between 211 gut microbiota taxa and brain tumors, using the largest existing gut microbiota Genome-Wide Association Studies meta-analysis data (n=13266) and combining it with brain tumor data in the IEU OpenGWAS database. We use inverse-variance weighted analysis, supplemented by methods such as Mendelian randomization-Egger regression, weighted median estimator, simple mode, and weighted mode, to assess causality. In addition, we also conducted the Mendelian randomization-Egger intercept test, Cochran's Q test, and Mendelian randomization Steiger directionality test to ensure the accuracy of the analysis. Quality control includes sensitivity analysis, horizontal gene pleiotropy test, heterogeneity test, and MR Steiger directionality test. Result: Our study found that specific gut microbial taxa, such as order Lactobacillales and family Clostridiaceae1, were positively correlated with the occurrence of brain tumors, while genus Defluviitaleaceae UCG011 and genus Flavonifractor were negatively correlated with the occurrence of brain tumors. The Mendelian randomization-Egger intercept test showed that our analysis was not affected by pleiotropy (P>0.05). Conclusion: This study reveals for the first time the potential causal relationship between gut microbiota and brain tumors, providing a new perspective for the prevention and treatment of early brain tumors. These findings may help develop new clinical intervention strategies and point the way for future research.

Discussion on the relationship between gut microbiota and glioma through Mendelian randomization test based on the brain gut axis.

BACKGROUND: In the realm of Gut-Brain axis research, existing evidence points to a complex bidirectional regulatory mechanism between gut microbiota and the brain. However, the question of whether a causal relationship exists between gut microbiota and specific types of brain tumors, such as gliomas, remains unresolved. To address this gap, we employed publicly available Genome-Wide Association Study (GWAS) and MIOBEN databases, conducting an in-depth analysis using Two-Sample Mendelian Randomization (MR). METHOD: We carried out two sets of MR analyses. The preliminary analysis included fewer instrumental variables due to a high genome-wide statistical significance threshold (5×10-8). To enable a more comprehensive and detailed analysis, we adjusted the significance threshold to 1×10-5. We performed linkage disequilibrium analysis (R2 <0.001, clumping distance = 10,000kb) and detailed screening of palindromic SNPs, followed by MR analysis and validation through sensitivity analysis. RESULTS: Our findings reveal a causal relationship between gut microbiota and gliomas. Further confirmation via Inverse Variance Weighting (IVW) identified eight specific microbial communities related to gliomas. Notably, the Peptostreptococcaceae and Olsenella communities appear to have a protective effect, reducing glioma risk. CONCLUSION: This study not only confirms the causal link between gut microbiota and gliomas but also suggests a new avenue for future glioma treatment.

Role of gut microbiota in regulating immune checkpoint inhibitor therapy for glioblastoma.

Glioblastoma (GBM) is a highly malignant, invasive, and poorly prognosed brain tumor. Unfortunately, active comprehensive treatment does not significantly prolong patient survival. With the deepening of research, it has been found that gut microbiota plays a certain role in GBM, and can directly or indirectly affect the efficacy of immune checkpoint inhibitors (ICIs) in various ways. (1) The metabolites produced by gut microbiota directly affect the host's immune homeostasis, and these metabolites can affect the function and distribution of immune cells, promote or inhibit inflammatory responses, affect the phenotype, angiogenesis, inflammatory response, and immune cell infiltration of GBM cells, thereby affecting the effectiveness of ICIs. (2) Some members of the gut microbiota may reverse T cell function inhibition, increase T cell anti-tumor activity, and ultimately improve the efficacy of ICIs by targeting specific immunosuppressive metabolites and cytokines. (3) Some members of the gut microbiota directly participate in the metabolic process of drugs, which can degrade, transform, or produce metabolites, affecting the effective concentration and bioavailability of drugs. Optimizing the structure of the gut microbiota may help improve the efficacy of ICIs. (4) The gut microbiota can also regulate immune cell function and inflammatory status in the brain through gut brain axis communication, indirectly affecting the progression of GBM and the therapeutic response to ICIs. (5) Given the importance of gut microbiota for ICI therapy, researchers have begun exploring the use of fecal microbiota transplantation (FMT) to transplant healthy or optimized gut microbiota to GBM patients, in order to improve their immune status and enhance their response to ICI therapy. Preliminary studies suggest that FMT may enhance the efficacy of ICI therapy in some patients. In summary, gut microbiota plays a crucial role in regulating ICIs in GBM, and with a deeper understanding of the relationship between gut microbiota and tumor immunity, it is expected to develop more precise and effective personalized ICI therapy strategies for GBM, in order to improve patient prognosis.

Intracranial caseating granulomas with no infectious organism detected.

BACKGROUND: Caseating granuloma is a classic histopathological feature of mycobacterial infections. Occasionally, no infectious organism is demonstrated despite extensive examination of intracranial caseating granulomas. The pathogenesis and optimal management strategy for patients with such intracranial caseating granulomas with no detectable infectious organism (ICGNs) remain unclear. METHODS: The study was a retrospective case-series design in a referral hospital setting. Patients with intracranial caseating granulomas in whom no infectious etiology was identified after appropriate investigations were reviewed. RESULTS: Eight patients with ICGN (four females and four males) were identified in an eight-year-period. Average age on presentation was 46 years (range 21-69 years). Cerebrospinal fluid showed lymphocytic pleocytosis, elevated protein and decreased glucose. Neuroimaging showed multiple or single intraparenchymal and meningeal enhancements. Intracranial ICGN were demonstrated on biopsy. Immunomodulation was tried and resulted in improvement in five out of eight patients. In four patients, anti-mycobacterial treatment resulted in no improvement or worsening of clinical or radiological features. CONCLUSIONS: The response to therapy of intracranial caseating granulomas where no organism is identified after thorough investigations hints to non-infectious causes, and suggests current dogma regarding the significance of necrosis in granulomatous diseases should be re-evaluated. Our retrospective series suggests that patients may benefit from an early trial of immunomodulation therapy, a hypothesis to be tested in a randomized trial.

Glioma and temozolomide induced alterations in gut microbiome.

The gut microbiome is fundamental in neurogenesis processes. Alterations in microbial constituents promote inflammation and immunosuppression. Recently, in immune-oncology, specific microbial taxa have been described to enhance the effects of therapeutic modalities. However, the effects of microbial dysbiosis on glioma are still unknown. The aim of this study was to explore the effects of glioma development and Temozolomide (TMZ) on fecal microbiome in mice and humans. C57BL/6 mice were implanted with GL261/Sham and given TMZ/Saline. Fecal samples were collected longitudinally and analyzed by 16S rRNA sequencing. Fecal samples were collected from healthy controls as well as glioma patients at diagnosis, before and after chemoradiation. Compared to healthy controls, mice and glioma patients demonstrated significant differences in beta diversity, Firmicutes/Bacteroides (F/B) ratio, and increase of Verrucomicrobia phylum and Akkermansia genus. These changes were not observed following TMZ in mice. TMZ treatment in the non-tumor bearing mouse-model diminished the F/B ratio, increase Muribaculaceae family and decrease Ruminococcaceae family. Nevertheless, there were no changes in Verrucomicrobia/Akkermansia. Glioma development leads to gut dysbiosis in a mouse-model, which was not observed in the setting of TMZ. These findings seem translational to humans and warrant further study.

Permissive microbiome characterizes human subjects with a neurovascular disease cavernous angioma.

Cavernous angiomas (CA) are common vascular anomalies causing brain hemorrhage. Based on mouse studies, roles of gram-negative bacteria and altered intestinal homeostasis have been implicated in CA pathogenesis, and pilot study had suggested potential microbiome differences between non-CA and CA individuals based on 16S rRNA gene sequencing. We here assess microbiome differences in a larger cohort of human subjects with and without CA, and among subjects with different clinical features, and conduct more definitive microbial analyses using metagenomic shotgun sequencing. Relative abundance of distinct bacterial species in CA patients is shown, consistent with postulated permissive microbiome driving CA lesion genesis via lipopolysaccharide signaling, in humans as in mice. Other microbiome differences are related to CA clinical behavior. Weighted combinations of microbiome signatures and plasma inflammatory biomarkers enhance associations with disease severity and hemorrhage. This is the first demonstration of a sensitive and specific diagnostic microbiome in a human neurovascular disease.

Use of transgenic mice reveals cell-specific transformation by a simian virus 40 T-antigen amino-terminal mutant.

We have used the multifunctional transforming protein, simian virus 40 T antigen, as a probe to study the mechanisms of cell growth regulation in the intact organism. T antigen appears to perturb cell growth, at least in part, by stably interacting with specific cellular proteins that function to maintain normal cell growth properties. Experiments in cultured cells indicate that at least three distinct regions of simian virus 40 T antigen have roles in transformation. Two regions correlate with the binding of known cellular proteins, p53, pRB, and p107. A third activity, located near the amino terminus, has been defined genetically but not biochemically. By targeting expression of wild-type and mutant forms of T antigen to distinct cell types in transgenic mice, we have begun to systematically determine which activities play a role in tumorigenesis of each cell type. In this study, we sought to determine the role of the amino-terminal transformation function with such an analysis of the T-antigen mutant dl1135. This protein, which lacks amino acids 17 to 27, retains the p53-, pRB-, and p107-binding activities yet fails to transform cells in culture. To direct expression in transgenic mice, we used the lymphotropic papovavirus transcriptional signals that are specific for B and T lymphocytes and the choroid plexus epithelium of the brain. We show here that although defective in cell culture, dl1135 specifically induced the development of thymic lymphomas in the mouse. Expression of the protein was routinely observed in B- and T-lymphoid cells, although B-cell abnormalities were not observed. Choroid plexus tumors were observed only infrequently; however, dl1135 was not consistently expressed in this tissue. Within a given transgenic line, the penetrance of T-cell tumorigenesis was 100% but appeared to require secondary events, as judged from the clonal nature of the tumors. These experiments suggest that the amino-terminal region of T antigen has a role in the transformation of certain cell types (such as fibroblasts in culture and B lymphocytes) but is dispensable for the transformation of T lymphocytes.

Nontuberculous mycobacterial infection of a metastatic brain neoplasm in an immunocompromised patient.

BACKGROUND: Nontuberculous mycobacterial infections occur in immunocompromised patients but so rarely involve the central nervous system (CNS) that they may not be included in a differential diagnosis of CNS lesions in such patients. OBJECTIVE: To illustrate a putative mechanism for nontuberculous mycobacterial infection of the CNS via breakdown of the blood-brain barrier by metastatic neoplasm. RESULTS: A 56-year-old man who had undergone renal transplantation in February 2003 and was taking an immunosuppressive regimen of mycophenolate mofetil and cyclosporine was seen in the emergency department after a syncopal episode. Head computed tomography revealed a single focal occipital lesion with vasogenic edema. Hospital admission and further workup led to diagnosis of metastatic carcinoma infected with nontuberculous mycobacteria in the setting of a disseminated nontuberculous mycobacterial infection. CONCLUSION: This case illustrates that breakdown of the blood-brain barrier by metastatic neoplasm may provide a route of access for a pathogen that is not normally seen in the CNS.

R-type virus-like particles in avian sarcoma virus-induced rat central nervous system tumors.

Morphologically distinct virus-like particles (VLP), similar to R-type VLP, were observed by electron microscopy in experimental rat central nervous system tumors induced with the B-77-C strain of avian sarcoma virus (ASV). R-type VLP have a characteristic internal radial structure and were observed previously only in hamster cells and in an established bovine cell line. They were not observed in the B-77 ASV inoculum used to induce the rat tumors or in the B-77 induced hamster glioma cells from which the B-77 was rescued. Nevertheless, the genome of an endogenous hamster R-type particle also might have been rescued and carried in the B-77 inoculum. Alternatively, R-type VLP may exist in a number of animal species, including the rat, and may be expressed in certain conditions such as neoplastic transformation.

Polyoncogenicity and insulinoma-inducing ability of BK Virus, a human Papovavirus, in Syrian golden hamsters.

Newborn hamsters were inoculated intracerebrally with a series of purified and concentrated BK virus samples originating from a single stock of Gardner's original strain. Most (60-100%) of the hamsters developed various tumors 3-9 months later. The frequent types of tumors were ventricular tumors (choroid plexus papillomas and ependymomas: 7-53%), malignant insulinomas (0-92%), and osteosarcomas (0-50%). The T-antigen was positive in 59 of 60 tumors tested, but the virus was rescued by the cell fusion method from only 1 of 11 cell lines derived from these tumors. The incidence of insulinomas varied greatly with the virus sample; the two samples that showed the highest incidence (47 and 92%) originated from one parental virus stock, and all the other samples with the lower incidences (0-9%) originated from another ancestral stock. These results suggest the presence of a BK virus mutant(s) differing in capacity to induce insulinoma. A functional insulinoma cell line was thus established.

Amount of satellite DNA in four experimentally induced tumors of the central nervous system. Quantitative changes in a glioblastoma producing C-type particles.

The quantitative preservation of satellite NA was studied in several central nervous system (CNS) neoplasms; four tumor lines deriveo from 3-methylcholanthrene implantation into the CNS of mice were compared with brain and tissue cultures of normal mouse cells by analytical centrifugation in cesium chlorie. Three tumors showed no detectable difference from normal cells; nuclear and whole cell preparations were comparable. Only a glioblastoma line proucing C-type particles (TC509) revealed a significant difference from normal cells and exhibited a decrease of approximately 20% in satellite DNA or 2% of the total DNA on repeated examination for 1 year. C-type RNA virus may be related to relative decreases in satellite DNA observed in TC509.

Spatial distribution of proliferating cells in avian sarcoma virus-induced gliomas.

We studied the regional distribution of proliferating tumor cells in five avian sarcoma virus-induced gliomas. The labeling index and spatial distribution of [3H]thymidine (dThd)-labeled tumor cells were determined in serial sections of each tumor with a computer-assisted digitizing system. The density of [3H]dThd-labeled cells showed marked regional variation in each tumor, and the ratio of the density of [3H]dThd-labeled cells in tumor periphery to tumor center varied from 0.86 to 1.38. The labeling index generally, but not always, reflected [3H]dThd-labeled cell density. This study indicates that proliferating pools of glioma tumor cells exhibit regional variability in concentration and that the highest numbers of proliferating cells may be predominantly located in central regions of tumor and not in tumor periphery as assumed previously. In all tumors, large numbers of proliferating cells were present in all parts of the tumor.

Brain tumours and lymphomas in transgenic mice that carry HTLV-I LTR/c-myc and Ig/tax genes.

The human T-cell leukemia virus type 1 (HTLV-I) is associated with adult CD4+ T-cell leukemia (ATL) and tropical spastic paraparesis (TSP). In as much as only a small percentage of individuals infected with HTLV-I develop either disease, we set out to model a genetic partner for this virus in an effort to understand and possibly reproduce its pathophysiology. To this end we have developed a binary set of transgenic mice, one bearing the relatively inactive HTLV-I long terminal repeat (LTR) positioned to drive the c-myc oncogene and another bearing a fusion transgene consisting of the immunoglobulin promoter/enhancer driving the gene for the HTLV-I transcription activator, tax. Alone, the tax construct, though expressed in the thymus, spleen, lung and brain, has no deleterious effect. Alone, the HTLV-I LTR/c-myc construct is expressed at very low levels in lymphoid cells and occasionally induces lymphomas in older animals. When these two transgenic lines are mated, bigenic offspring harboring both transgenes exhibit dramatic tumor formation. As in the human, these animals develop CD4+ T-cell lymphomas, but they also develop central nervous system tumors by 25-90 days of age. The syndrome, which is 100% penetrant and lethal, provides an animal model for adult T-cell lymphoma and a source of cultured cells of neurogenic origin.